This is a resubmission of proposal 2R01 CA40081-05A1. The principal goal of our research program is to develop efficient, stereocontrolled synthetic routes to biologically important cyclodepsipeptides and to study their potential sites of activity. We have previously investigated the chemistry and synthesis of the didemnins. A significant accomplishment during this period was the revision of the stereochemistry of the Hip unit. We have also developed a general synthetic strategies and methodologies that will enable us to make modifications, either in the macrocycle or in the linear side chains. These side chains are of utmost importance for biological activity. Our synthetic approach id eminently suited for modifying amino acids in the peptide chain, and to, therefore, examine specific aspects of the structure-activity relationships (SARs). SARs are important, not only for the design of improved drugs, but also for better understanding of the mechanism of bioactivity. Using molecular modeling programs and chemical intuition, we have designed some analogs as reasonable entry targets and we have devised strategies for their construction. The planned investigations will also contribute to the development of biologically important cyclodepsipeptides. The structural simplicity of the didemnins, their potent and diverse biological activities, and their present scarcity make synthetic investigations of these compounds an important endeavor.